Abstract Diabetic retinopathy remains the leading cause of blindness in working age adults. Currently, there are no approved and demonstrated treatments for diabetic retinopathy aside from insulin replacement therapy and blood pressure control. Recent longitudinal study reports have demonstrated that despite achieving stable blood glucose levels and HbA1c control, patients formerly under non-intensive insulin therapy continue to have a higher rate of developing diabetic retinopathy, and other complications. This provides the first large-scale clinical evidence for the hypothesis of metabolic memory, in which a period of poor diabetes management continues to impact development of retinopathy and other complications for years after good control has been achieved. Understanding the role of metabolic memory in complication development is vitally needed as the memory phenomenon is obviously not overcome by current treatment regimens. This clinical phenomenon also leads to the questions of what molecular events occur during poor control and how do these events persist for years after good glycemic control is established. This proposal seeks to address this issue through an investigation of the hypothesis that poor control causes epigenomic changes that are not fully reversed with improved diabetes management. In the proposed studies we will define retinal gene promoter DNA methylation and associated chromatin modifications in the context of diabetes with variable glycemic control. We will then use bioinformatic tools to compare the epigenetic state to retinal gene/protein expression. Epigenetic changes will be confirmed by orthogonal methods and the resulting transcript and protein expression changes will be localized to specific retinal layers and cell types. Lastly the processes that regulate DNA methylation and histone modification will be examined. These studies will serve as the basis for future interventional studies which seek to maintain or return the normal retina epigenetic state as well as mechanistic studies investigating how specific genes are targeted for epigenetic modifications during hyperglycemia.